This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The adaptive immune system has evolved several different lines of attack, each one optimally effective against a given pathogen. For example, in response to intracellular microbes, CD4+ T-helper cells (Th) differentiate into Th1 cells;in contrast helminths induce Th2 cells, whose cytokines (IL-4, IL-5 &IL-10) induce IgE and eosinophil-mediated destruction of the pathogens. Although these diverse responses have been characterized in detail, the mechanism by which a particular type of immune response is initiated is poorly understood. Analogous to the situation in Drosophila, signaling through distinct TLRs can yield qualitatively different immune responses. Furthermore, we suggest that different DC subsets are endowed with distinct, repertoires of pattern recognition receptors, which enable them to recognize distinct classes of pathogens, and initiate different types of immune responses. This research provides a novel mechanism by which distinct pathogens such as HIV can elicit distinct adaptive immunity, by targeting different cells of the innate immune system. Such results offer novel strategies for manipulating immune responses in clinical settings. Work in the past year has focused on defining subsets of antigen presenting cells, and the nature of the innate immune receptors that regulate the class of the immune responses against pathogens. Highlights include: + The demonstration that distinct subsets of antigen presenting cells differentially regulate T regulatory and Th17 cells. + The demonstration a novel mechanism by which viruses induce type I interferons in plasmacytoid dendritic cells. + The demonstration that systems biology tools can be used to predict immunity induced by vaccines such as yellow fever vaccine.